In mice, mutations at the microphthalmia (mi) locus on chromosome 6 may lead to abnormalities that include loss of coat pigmentation, hearing impairment, microphthalmia, and osteopetrosis. These abnormalities result from deficiencies in osteoclasts, retinal pigment cells, and neural crest-derived melanocytes of the skin and inner ear. Using a transgenic insertion at mi, we have recently isolated a gene that resides at this locus and encodes a novel member of the basic-helix-loop-helix-zipper class of transcription factors. In all mi alleles analyzed to date, this gene is mutated; in many of them, the nature of the mutation helps explain the mode of inheritance and the interactions between mi alleles that have been observed previously in compound heterozygotes. A detailed analysis of the expression of this gene suggests that mi plays an important role early in melanocyte development in eye, inner ear, and skin. To understand more precisely how mi exerts its pleiotropic effect on different cell populations, we have established culture systems in which cell proliferation and differentiation can be studied in conjunction with analysis of expression of mi and other genes. Mutations at mi may serve as models for human Waardenburg syndrome type II, a hereditary syndrome characterized by varying degrees of hearing impairment and pigment alterations. The recent isolation and chromosomal mapping of the human counterpart of mouse mi, MITF, may help to clarify the molecular basis of this disorder and possibly other forms of syndromic hearing loss. Another line of transgenic mice contains approximately 15 transgene copies integrated into an intron of the mouse mox1 gene that encodes a mesodermal homeodomain protein. Mice homozygous for this transgene integration lack expression of mox1 and show a phenotype characterized by atlanto-baso-occipital fusions, hemivertebrae, and short, kinky tails, but they are fertile and have a normal lifespan. Crosses with other mice with similar phenotypes but mutations in different genes, along with a detailed study of the expression of mox1 and other genes, will help to place mox1 into a genetic hierarchy of factors involved in the development of the vertebra and skull. Mox1 is localized on distal chromosome 11 near Tail short (Ts), a locus whose mutations are also associated with short, kinky tails. Whether Ts and mox1 are identical is currently being tested.